The delivery of small molecules across biological membranes has been a long-standing challenge to medicinal chemistry. Several drugs that are highly effective in vitro are incompatible with the transport mechanisms of the human organism as the cell membrane proves to be impenetrable. The delivery of such drugs could be facilitated by carefully designed synthetic receptors, with natural receptors serving as an inspiration for design. It was recently demonstrated that resorcinarene cavitands are capable of behaving as selective receptors for small-molecule guests while localized in aqueous phosphocholine (PC) micelles. PC micelles serve as a useful tool for the direct observation of host and guest interaction, but they fall short of approximating biological membranes. Lipid vesicles on the other hand, serve as a more realistic model. This project aims to prepare a series of mono-functionalized resorcinarene cavitands that can be fluorescently tagged to study the transport of fluorescently tagged receptor-complementary small molecules across ordered lipid assemblies. Cavitands and small molecule guests will be introduced into unilamellar vesicles and confocal microscopy will be utilized to evaluate successful membrane localization and transport. The knowledge acquired from these initial studies will be applied to mammalian cell membranes. Using fluorescently tagged cavitands we will be able to evaluate a variety of cavitands for cell membrane localization. These results will lead to new insights and hypotheses that can be deployed towards cell based assays to explore previously membrane resistant drug candidates. Additionally, new "nano-medicinal" approaches support exploring roles in which polycationic cavitands can serve as direct genetic transfection vectors. These new approaches to selective molecular transport will provide exciting opportunities towards advancing current drug delivery methods and designing nanoscale medical devices. PUBLIC HEALTH RELEVANCE: Annually, several promising clinically relevant compounds are discovered using in vitro techniques, only later to be dismissed due to an inability to penetrate the cell membrane. We aim to overcome this problem through the development of synthetic receptors that are suitable to selectively shuttle fluorophores and small drug like molecules across simplified lipid bilayers. Ultimately, we hope to use this information to develop receptors that are compatible with cellular systems and one day provide a means to overcoming what remains a major hurdle for medicinal chemistry and the effective treatment of human disease.